Imatinib ([4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]phenyl]benzamide) is a synthetic tyrosine kinase (TK) signal transduction inhibitor used for the treatment of a variety of chronic myeloid leukemia (CML) attributed to the Philadelphia chromosome–positive trait (1). This chromosomal abnormality develops after a genetic translocation between chromosome 9 and chromosome 22, which leads to the expression of an abnormal bcr-abl TK that is no longer dependent on normal activation as a result of the interaction between interleukin-3 and its receptor. This drug is also used for the treatment of gastrointestinal stromal tumors (GIST) that are caused by mutations in the closely related c-kit or platelet-derived growth factor (PDGF) TKs (2). In addition, imatinib has been shown to be an effective treatment against a variety of other conditions that are characterized by the expression of abl, c-kit, or PDGF TKs (3). Although imatinib is a useful chemotherapeutic agent for the treatment of CML and GIST, patients undergoing therapy for these conditions often develop resistance to the drug as a result of secondary mutations in the TKs.
The FDA approved imatinib for the treatment of CML in May 2001 and subsequently for the treatment of GIST in January 2002 (4). A detailed description of the indications for which imatinib can be prescribed is available in the product insert from the manufacturer (5).
In an attempt to initiate understanding of the development of drug resistance to imatinib, an N-[11C]-methyl derivative of imatinib was synthesized. The radiolabeled compound was then administered to baboons (Papio anubis) to determine drug biodistribution and pharmacokinetics in the animals (3).